Bacterial diarrhea is a major world health problem and one of the leading killers of children in the developing world. It is estimated that 1.9 million children worldwide die every year due to complications from enteropathogenic bacterial infection.
Bacterial diarrhea infections are prominent in developing nations and their impact has dramatically increased in the past decades in industrialized countries due to increase food processing, and due to the ease of worldwide travel. Virulent strains of Escherichia coli (E. coli) such as enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), enterinvasive E. coli (EIEC) and enterohemorrhagic E. coli (EHEC) are responsible for a significant proportion of bacterial enteric infections. While infections with EPEC cause infantile diarrhea, EHEC, an emerging zoonotic pathogen causes diarrhea that can lead to hemorrhagic colitis and hemolytic uremic syndrome. EPEC, ETEC, EIEC and EHEC, as well as other known bacterial pathogens, such as Salmonella and Shigella, for example, remain serious threats to human health. Of importance is that rotaviral diarrhea is at top of list of fatal diarrheal diseases.
Diarrheal diseases are the second leading cause of infant mortality world-wide. They kill due to dehydration from intestinal loss of water and electrolytes. A critical lack in current diarrheal therapy is availability of a drug that can stimulate intestinal Na+ absorption. In the human small intestine, the Na+/H+ Exchanger Isoform 3 (NHE3) protein accounts for the majority of Na+ absorption and is inhibited in both inflammatory and enterotoxigenic diarrheas. While chloride secretion leads to massive fluid loss in some diarrheal diseases such as cholera, inhibition of Na absorptions occurs in almost all diarrheal diseases.
There still exists, therefore, an unmet need for improved treatments for gastrointestinal diseases such as diarrhea.